Roles of Combined Glypican-3 and Glutamine Synthetase in Differential Diagnosis of Hepatocellular Lesions

Background: Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and thirdly leading causeof cancer-related death worldwide. The estimated risk of hepatocellular carcinoma is 15 to 20 times as highamong persons infected with HCV as it is among those who are not infected, with most of the excess risk limitedto those with advanced hepatic fibrosis or cirrhosis. Glypican3 (GPC3) plays a key role in relation to signalingwith growth factors, regulating the proliferative activity of cancer cells. Glutamine synthetase (GS) catalyzesthe synthesis of glutamine from glutamate and ammonia in the mammalian liver. GS was suggested as a specificmarker for tracing cell lineage relationships during hepatocarcinogenesis. In normal liver, GS expression isseen in pericentral hepatocytes, but not by midzonal or periportal hepatocytes. In HCC, strong and diffuseGS expression in seen in tumor cells.
Results: Glypican3 immunopositvity was highly specific and sensitiveindicator for hepatocellular carcinoma as well as glutamine synthetase which was found to be a sensitive andspecific indicator for development of hepatocellular carcinoma when compared to cirrhosis, liver cell dyspalsiaand metastatic carcinomas. Statistical analysis revealed a significant association between GPC3 and GS withtumor size (P=0.003, p=0.006, respectively). Diffuse staining significantly associated with large tumor size while,focal and mixed staining was detected more with small tumor size. Studying the relation with tumor grade alsorevealed significant association between diffuse GPC3 and GS staining with high tumor grade. Diffuse stainingwas detected in 91.7% and 100% respectively of poorly differentiated specimens and only in 33.3% and 22.2%of well differentiated specimens.
Conclusions: While using GPC3 and GS to screen for premalignant hepaticlesions remains controversial, our data suggest that GPC3 and GS may be a reliable diagnostic immunomarkersto distinguish HCC from benign hepatocellular lesions. However, negative immunostaining should not excludethe diagnosis of HCC.